Frailty is geriatric syndrome of increased vulnerability to stressors that leads to physical deterioration and a significant economic burden to the health care system. Key components of frailty include loss of muscle mass and quality (sarcopenia) and unintentional weight loss resulting from a mismatch between energy intake and expenditure. There are currently no approved therapies for frailty. As increasing numbers of individuals survive to their 80's and 90's, it is imperative to develop therapies that improve the health and quality of life of frail individuals. Ghrelin is a hormone produced by the stomach that stimulates appetite centers in the brain. It has been studied in over 300 humans, including those with specific diseases that cause cachexia (e.g. renal failure, cancer), but not in frail individuals. The overall purpose of this exploratory, developmental R21 is to gather the essential data and experience in preparation for a clinical trial of ghrelin and resistance training. We hypothesize that a joint intervention of ghrelin plus home-based resistance training will improve strength and lower extremity function in frail older individuals. In the proposed R21, we seek to examine the feasibility and obtain data on the safety and efficacy of this intervention in frail men and women aged 70 and older. In Aim 1, we will determine the optimal subcutaneous ghrelin dose in frail individuals. In Aim 2, we will examine this dose in a 7-day repeated daily dose study. In Aim 3, we will execute a 12 week pilot study of a home-based strength training intervention with and without ghrelin administration in frail individuals. This study will be the first to examine subcutaneous ghrelin administration in frail individuals, by itself and combined with resistance training. Our study will provide essential data to refine a future clinical trial to test ghrelin and resistance training as a joint intervention to improve the health and function of individuals with frailty. PUBLIC HEALTH RELEVANCE: There are currently no approved therapies to treat frailty in the elderly. Our study will examine the use of the hormone ghrelin, which stimulates appetite, in conjunction with resistance training to improve strength and function in frail older individuals.